Atypical features of the disordered N-terminal region of a bacterial outer membrane copper transporter
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Metals like copper (Cu), zinc, and nickel exhibit dual nature, necessitating a tight regulation of their cellular homeostasis to meet physiological demands while preventing toxicity. In bacteria, metal homeostasis involves inner membrane (IM) P-type ATPases and ABC transporters, envelope-spanning tripartite efflux pumps, and outer membrane (OM) pore-forming proteins.
Four decades ago, the OM β-barrel protein PcoB was shown to provide an additional layer of Cu resistance in an Escherichia coli strain isolated from the gut of swine fed with Cu supplements. Interestingly, most PcoB homologs contain a poorly conserved disordered N-terminal domain (NTD) rich in histidine (His) and methionine (Met) residues, which are commonly associated with Cu coordination in cuproproteins. This suggests a potential role for the NTD in PcoB-mediated copper efflux.
We previously demonstrated that the free-living bacterium Caulobacter vibroides primarily relies on PcoB for Cu homeostasis. Here, we show that the NTD of C. vibroides PcoB is critical for PcoB function and stability, tolerating the swapping with the poorly conserved E. coli PcoB NTD and significant truncations. Unexpectedly, the predicted signal peptide (SP) was dispensable, challenging traditional concepts of protein translocation mechanisms. Moreover, the PcoB NTD plays a surprising role in stabilizing the periplasmic multicopper oxidase PcoA, encoded within the same operon as PcoB, highlighting a new role for an intrinsically disordered region (IDR).
Importance
Bacterial copper (Cu) homeostasis is essential for survival in fluctuating environments, yet the role of single outer membrane proteins in this process remains poorly characterized. Our study reveals that the intrinsically disordered N-terminal region of the β-barrel protein PcoB in Caulobacter vibroides plays a critical role in Cu efflux and PcoB stability. Remarkably, this region harbors an atypical signal peptide and contributes to the stability of the periplasmic multicopper oxidase PcoA, suggesting a novel regulatory function for an intrinsically disordered region. These findings challenge existing paradigms of protein targeting and homeostasis, with broad implications for understanding bacterial adaptation to stress.
